Heterozygous Truncating Variants in POMP Escape Nonsense-Mediated Decay and Cause a Unique Immune Dysregulatory Syndrome

Am J Hum Genet. 2018 Jun 7;102(6):1126-1142. doi: 10.1016/j.ajhg.2018.04.010.

M Cecilia Poli ¹, Frédéric Ebstein ², Sarah K Nicholas ³, Marietta M de Guzman ³, Lisa R Forbes ⁴, Ivan K Chinn ³, Emily M Mace ³, Tiphanie P Vogel ³, Alexandre F Carisey ³, Felipe Benavides ⁵, Zeynep H Coban-Akdemir ⁶, Richard A Gibbs ⁷, Shalini N Jhangiani ⁸, Donna M Muzny ⁸, Claudia M B Carvalho ⁶, Deborah A Schady ⁹, Mahim Jain ⁶, Jill A Rosenfeld ⁶, Lisa Emrick ¹⁰, Richard A Lewis ¹¹, Brendan Lee ⁶, Undiagnosed Diseases Network members, Barbara A Zieba ², Sébastien Küry ¹², Elke Krüger ², James R Lupski ¹³, Bret L Bostwick ¹⁴, Jordan S Orange ¹⁵

Affiliations

1 Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Division of Pediatric Immunology, Allergy, and Rheumatology, Houston, TX 77030, USA; Instituto de Ciencias e Innovación en Medicina, Universidad del Desarrollo, Clínica Alemana de Santiago, RM 7590943, Chile.
2 Universitätsmedizin Greifswald, Institut für Medizinische Biochemie und Molekularbiologie, 17475 Greifswald, Germany.
3 Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Division of Pediatric Immunology, Allergy, and Rheumatology, Houston, TX 77030, USA.
4 Texas Children's Hospital, Division of Pediatric Immunology, Allergy, and Rheumatology, Houston, TX 77030, USA.
5 Instituto de Ciencias e Innovación en Medicina, Universidad del Desarrollo, Clínica Alemana de Santiago, RM 7590943, Chile.
6 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
7 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
8 Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
9 Texas Children's Hospital, Department of Pathology and Immunology, Houston, TX 77030, USA.
10 Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA.
11 Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Ophthalmology, Baylor College of Medicine, Houston, TX 77030, USA.
12 Centre Hospitalier Universitaire de Nantes Hôtel-Dieu, Institut de Biologie, Service de Génétique Médicale, Laboratoire de Génétique Moléculaire, 44093 Nantes Cedex 1, France.
13 Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
14 Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
15 Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Division of Pediatric Immunology, Allergy, and Rheumatology, Houston, TX 77030, USA. Electronic address: orange@bcm.edu.

PMID: 29805043 DOI: 10.1016/j.ajhg.2018.04.010

Abstract

The Proteasome processes proteins to facilitate immune recognition and host defense. When inherently defective, it can lead to aberrant immunity resulting in a dysregulated response that can cause autoimmunity and/or autoinflammation. Biallelic or digenic loss-of-function variants in some of the Proteasome subunits have been described as causing a primary immunodeficiency disease that manifests as a severe dysregulatory syndrome: chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE). Proteasome maturation protein (POMP) is a chaperone for Proteasome assembly and is critical for the incorporation of catalytic subunits into the Proteasome. Here, we characterize and describe POMP-related autoinflammation and immune dysregulation disease (PRAID) discovered in two unrelated individuals with a unique constellation of early-onset combined immunodeficiency, inflammatory neutrophilic dermatosis, and autoimmunity. We also begin to delineate a complex genetic mechanism whereby de novo heterozygous frameshift variants in the penultimate exon of POMP escape nonsense-mediated mRNA decay (NMD) and result in a truncated protein that perturbs Proteasome assembly by a dominant-negative mechanism. To our knowledge, this mechanism has not been reported in any primary immunodeficiencies, autoinflammatory syndromes, or autoimmune diseases. Here, we define a unique hypo- and hyper-immune phenotype and report an immune dysregulation syndrome caused by frameshift mutations that escape NMD.

Keywords

PID; POMP; POMP-related autoinflammation and immune dysregulation disease; PRAID; autoinflammatory syndrome; core particle proteasome 20S; dominant negative; interferonopathy; nonsense-mediated decay; primary immune deficiency.

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